OP0595, a new diazabicyclooctane: Mode of action as a serine beta-lactamase inhibitor, antibiotic and beta-lactam 'enhancer'

Morinaka, Akihiro, Tsutsumi, Yuko, Yamada, Mototsugu, Suzuki, Kenji, Watanabe, Takashi, Ida, Takao, Furuuchi, Takeshi, Inamura, Seiichi, Sakamaki, Yoshiaki, Mitsuhashi, Nakako, Mitsuhashi, Nakako, Ida, Takashi and Livermore, David (2015) OP0595, a new diazabicyclooctane: Mode of action as a serine beta-lactamase inhibitor, antibiotic and beta-lactam 'enhancer'. Journal of Antimicrobial Chemotherapy, 70 (10). pp. 2779-2786. ISSN 0305-7453

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Abstract

Objectives: The production of a growing diversity of b-lactamases by Gram-negative bacteria challenges antimicrobial chemotherapy. OP0595, discovered separately by each of Meiji Seika Pharma and Fedora Pharmaceuticals, is a new diazabicyclooctane serine b-lactamase inhibitor that also acts as an antibiotic and as a b-lactamase-independent b-lactam ‘enhancer’. Methods: Inhibitory activity against serine b-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with b-lactam agents were measured according to CLSI recommendations. Morphological changes in Escherichia coli were examined by phase-contrast microscopy. Results: IC50s of OP0595 for class A and C b-lactamases were ,1000 nM, with covalent binding demonstrated to the active-site serine of CTX-M-44 and AmpC enzymes. OP0595 also had direct antibiotic activity against many Enterobacteriaceae, associated with inhibition of PBP2 and conversion of the bacteria into spherical forms. Synergy between OP0595 and b-lactam agents was seen against strains producing class A and C b-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner b-lactam agents for a non-blactamase-producing E. coli mutant that was resistant to OP0595 itself, indicating b-lactamase-independent ‘enhancer’-based synergy. Conclusions: OP0595 acts in three ways: (i) as an inhibitor of class A and C b-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an ‘enhancer’ of b-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various b-lactam agents.

Item Type: Article
Uncontrolled Keywords: enterobacteriaceae,antibiotic resistance,penicillin-binding proteins
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 24 Jul 2015 23:01
Last Modified: 22 Jul 2020 00:19
URI: https://ueaeprints.uea.ac.uk/id/eprint/53794
DOI: 10.1093/jac/dkv166

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